Abstract

Background: Observational associations between cannabis and
schizophrenia are well documented, but ascertaining causation is more challenging.
We used Mendelian randomization (MR), utilizing publicly available data as a method
for ascertaining causation from observational data.
Methods: We performed bi-directional two-sample MR using summary level
genomewide data from the International Cannabis Consortium (ICC) and the
Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs)
associated with cannabis initiation (P < 10-5) and schizophrenia (P < 5x10-8) were
combined using an inverse-variance weight fixed-effects approach. We also used
height and education genomewide-association study data, representing negative and
positive control analyses.
Results: There was some evidence consistent with a causal effect of
cannabis initiation on risk of schizophrenia (OR 1.04 per doubling odds of cannabis
initiation, 95% CI 1.01, 1.07, P = 0.019). There was strong evidence consistent with a
causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per
doubling of the odds of schizophrenia, 95% CI 1.05, 1.14, P = 2.64 × 10-5). Findings
were as predicted for the negative control (height OR 1.00, 95% CI 0.99 to 1.01, P =
0.90) but weaker than predicted for the positive control (years in education OR 0.99,
95% CI 0.97 to 1.00, P = 0.066) analyses.
Conclusions: Our results provide some that cannabis initiation increases the
risk of schizophrenia, though the size of the causal estimate is small. We find
stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as
genetic instruments for schizophrenia are stronger than for cannabis initiation.